Prokineticin receptor 1 (PKR1) and its ligand Bv8 were shown to be expressed in inflammation-induced pain and by tumorsupporting fibroblasts. Blocking this receptor might prove useful for reducing pain and for cancer therapy. However, there is no method to quantify the levels of these receptors in vivo. Methods: A nonpeptidic PKR1 antagonist, N-{2-[5-(4-fluorobenzyl)- 1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]- ethyl}-guanidine, which contains a free guanidine group, was labeled with 18F by reacting the guanidine function with N-succinimidyl-4- 18F-fluorobenzoate to give the guanidinyl amide N-(4- 18F-fluoro-benzoyl)-N9-{2-[5-(4-fluorobenzyl)- 1-(4-methoxy-benzyl)- 4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]-ethyl}-guanidine ( 18F-PC-10). Inflammation was induced in C57BL/6 mice by subcutaneous injection of complete Freund adjuvant in the paw. The mice were imaged with 18F-PC- 10, 18F-FDG, and 64Cu-pyruvaldehyde bis(4-methyl-3-thiosemicarbazone) (64Cu-PTSM) at 24 h after complete Freund adjuvant injection using a small-animal PET device. Results: 18F-PC-10 was synthesized with a radiochemical yield of 16% ± 3% (decay-corrected). 18F-PC-10 accumulated specifically in the inflamed paw 4- to 5-fold more than in the control paw. Compared with 18F-PC-10, 18F-FDG and 64Cu-PTSM displayed higher accumulation in the inflamed paw but also had higher accumulation in the control paw, demonstrating a reduced signal-to-background ratio. 18F-PC-10 also accumulated in PKR1-expressing organs, such as the salivary gland and gastrointestinal tract. Conclusion: 18F-PC-10 can be used to image PKR1, a biomarker of the inflammation process. However, the high uptake of 18F-PC-10 in the gastrointestinal tract, due to specific uptake and the metabolic processing of this highly lipophilic molecule, would restrict its utility. Copyright © 2011 the American Physiological Society.
Prokineticin Receptor 1 Antagonist PC-10 as a Biomarker for Imaging Inflammatory Pain
SALVADORI, Severo;
2011
Abstract
Prokineticin receptor 1 (PKR1) and its ligand Bv8 were shown to be expressed in inflammation-induced pain and by tumorsupporting fibroblasts. Blocking this receptor might prove useful for reducing pain and for cancer therapy. However, there is no method to quantify the levels of these receptors in vivo. Methods: A nonpeptidic PKR1 antagonist, N-{2-[5-(4-fluorobenzyl)- 1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]- ethyl}-guanidine, which contains a free guanidine group, was labeled with 18F by reacting the guanidine function with N-succinimidyl-4- 18F-fluorobenzoate to give the guanidinyl amide N-(4- 18F-fluoro-benzoyl)-N9-{2-[5-(4-fluorobenzyl)- 1-(4-methoxy-benzyl)- 4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]-ethyl}-guanidine ( 18F-PC-10). Inflammation was induced in C57BL/6 mice by subcutaneous injection of complete Freund adjuvant in the paw. The mice were imaged with 18F-PC- 10, 18F-FDG, and 64Cu-pyruvaldehyde bis(4-methyl-3-thiosemicarbazone) (64Cu-PTSM) at 24 h after complete Freund adjuvant injection using a small-animal PET device. Results: 18F-PC-10 was synthesized with a radiochemical yield of 16% ± 3% (decay-corrected). 18F-PC-10 accumulated specifically in the inflamed paw 4- to 5-fold more than in the control paw. Compared with 18F-PC-10, 18F-FDG and 64Cu-PTSM displayed higher accumulation in the inflamed paw but also had higher accumulation in the control paw, demonstrating a reduced signal-to-background ratio. 18F-PC-10 also accumulated in PKR1-expressing organs, such as the salivary gland and gastrointestinal tract. Conclusion: 18F-PC-10 can be used to image PKR1, a biomarker of the inflammation process. However, the high uptake of 18F-PC-10 in the gastrointestinal tract, due to specific uptake and the metabolic processing of this highly lipophilic molecule, would restrict its utility. Copyright © 2011 the American Physiological Society.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
